title: CDKAL1 and HHEX are associated with type 2 diabetes-related traits among Yup'ik people.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D), mainly among individuals of European ancestry. In the present study, we examined the frequency of these SNPs and their association with T2D-related traits in an Alaska Native study population with a historically low prevalence of T2D. We also investigated whether dietary characteristics that may protect against T2D, such as n-3 polyunsaturated fatty acid (PUFA) intake, modify these associations.
  
  
  METHODS
  In 1144 Yup'ik people, we examined 17 SNPs repeatedly identified in GWAS for individual and cumulative associations with T2D-related traits. Cumulative associations were evaluated using a genetic risk score (GRS) calculated by summing risk alleles. Associations were tested for interactions with sex, body mass index (BMI), and n-3 PUFA intake.
  
  
  RESULTS
  The rs7754840 SNP in CDKAL1 is significantly associated with HbA1c (P = 0.00091). The rs5015480 SNP near HHEX is significantly associated (in opposite direction to that in Europeans) with a combined fasting glucose (FG) and HbA1c measure (P = 0.00046) and with homeostatic model assessment of β-cell function (HOMA-B; P = 0.0014). The GRS is significantly associated with FG and combined FG and HbA1c only when the HHEX SNP is dropped from the GRS. Associations are not modified by BMI or n-3 PUFA intake.
  
  
  CONCLUSIONS
  Our results highlight the potential importance of CDKAL1 and HHEX in glucose homeostasis in this Alaska Native population with a low prevalence of T2D, and suggest that these loci should be examined in greater detail in this population.
authors.affiliation: Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
authors.forename: Yann C
authors.initials: YC
authors.lastname: Klimentidis
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Lemas
authors.forename: Howard H
authors.initials: HH
authors.lastname: Wiener
authors.forename: Diane M
authors.initials: DM
authors.lastname: O'Brien
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.forename: Kimber L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: Scarlett E
authors.initials: SE
authors.lastname: Hopkins
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: Bert B
authors.initials: BB
authors.lastname: Boyer
mesh_terms: D000328:Adult; D000413:Alaska / Q000453:epidemiology; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D004032:Diet; D005215:Fasting / Q000097:blood; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood; D004930:Inuit / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D012359:tRNA Methyltransferases
chemical_list: D001786:Blood Glucose; D051360:Cyclin-Dependent Kinase 5; D015525:Fatty Acids, Omega-3; D006442:Glycated Hemoglobin; D018398:Homeodomain Proteins; D007328:Insulin; D014157:Transcription Factors; D012359:tRNA Methyltransferases; C078492:HHEX protein, human; C525110:CDKAL1 protein, human
keywords: Alaska Native; glycemic traits; n-3 polyunsaturated fatty acids; type 2 diabetes single nucleotide polymorphisms; 阿拉斯加原住民，血糖特征，n-3多不饱和脂肪酸，2型糖尿病单核苷酸多态性